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STATISTICAL ANALYSIS PLAN
PROTOCOL ONX-2012-001
Phase 1b/2, Multicenter, Open–label Study of Oprozomib and Dexamethasone in Subjects with
Relapsed and/or Refractory Multiple Myeloma
Sponsor: Onyx Pharmaceuticals, an Amgen subsidiary
One Amgen Center Dr.
Thousand Oaks, CA 91320
(805) 447-4897
Date: OCT 20, 2016
Version: 1.0
Confidential Information
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be
disclosed unless such disclosure is required by applicable laws and regulations. In any event, persons to whom the information is
disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These
restrictions on disclosure will apply equally to all future information supplied to you which is indicated as privileged or confidential.
Date/Time of most recent changes: 10/20/2016
NCT Number: NCT01832727This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov
Onyx Pharmaceuticals Inc. Statistical Analysis Plan For Protocol ONX-2012-001
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Signature Page
Prepared by:
Date:
PhD Senior Manager, Biostatistics
Reviewed by:
Date:
PhD Director, Global Biostatistics
Date:
MD Medical Monitor: Oprozomib
Date:
PharmD Medical Sciences Director
Onyx Pharmaceuticals Inc.
Prepared by:
Reviewed by:
Statistical Analysis Plan For Protocol ONX-2012-001
Signature Page
Date: 2o OcT20/6 PhD
Senior Manager, Biostatistics
PhD Director, Global Biostatistics
-------------- Date:
MD Medical Monitor: Oprozomib
~------------~ Date: ~--------PharmD
Medical Sciences Director
page 2
Onyx Pharmaceuticals Inc.
Prepared by:
Reviewed by:
Statistical Analysis Plan For Protocol ONX-2012-001
Signature Page
PhD Senior Manager, Biostatistics
PhD Director, Global Biostatistics
MD Medical Monitor: Oprozomib
PharmD Medical Sciences Director
page 2
Onyx Pharmaceuticals Inc.
Prepared by:
Reviewed by:
Statistical Analysis Plan For Protocol ONX-2012-001
Signature Page
PhD Senior Manager, Biostatistics
PhD Director, Global Biostatistics
MD Medical Monitor: Oprozomib
page 2
i J
Onyx Pharmaceuticals Inc. Statistical Analysis Plan For Protocol ONX-2012-001
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LIST OF ABBREVIATIONS
Abbreviation or Term Definition
AE adverse event
CRF case report form
CBR clinical benefit response
CR complete response
CSR clinical study report
CTCAE Common Terminology Criteria for Adverse Events
DOR duration of response
ECOG Eastern Cooperative Oncology Group
MM multiple myeloma
MedDRA Medical Dictionary for Regulatory Activities
mg milligram
MTD maximum tolerated dose
N number of subjects
nCR near complete response
ORR overall response rate
PD progressive disease
PDn pharmacodynamic
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Abbreviation or Term Definition
PFS progression-free survival
PK Pharmacokinetic
PR partial response
PT MedDRA preferred term
SAE serious adverse event
SAP statistical analysis plan
sCR stringent complete response
SD stable disease
SOC MedDRA system organ class
TEAEs Treatment-emergent adverse events
TTP time to progression
VGPR very good partial response
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TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................ 7
2 STUDY OVERVIEW ....................................................................................... 7
2.1 Overall Study Design ............................................................................... 7
2.2 Study Objectives ...................................................................................... 8
2.2.1 Primary Objectives................................................................................... 8
2.2.2 Secondary Objectives............................................................................... 9
2.3 Sample Size Justification ......................................................................... 9
3 STUDY ENDPOINTS ................................................................................... 10
3.1 Primary Endpoints ................................................................................. 10
3.2 Secondary Endpoints ............................................................................. 10
4 ANALYSIS POPULATIONS ........................................................................ 11
5 ANALYTIC DEFINITIONS ........................................................................... 11
5.1 Study Day 1............................................................................................ 11
5.2 Study Day............................................................................................... 11
5.3 Baseline .................................................................................................. 12
6 INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES ................... 12
7 STATISTICAL METHODS ........................................................................... 12
7.1 General Considerations .......................................................................... 12
7.2 Disposition of Subjects .......................................................................... 13
7.3 Demographic and Baseline Characteristics ........................................... 13
7.3.1 Demographic and Baseline Characteristics ........................................... 13
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7.3.2 Medical History ..................................................................................... 14
7.3.3 Disease Characteristics .......................................................................... 14
7.3.4 Prior Cancer Therapies .......................................................................... 15
7.4 Treatments and Medications .................................................................. 15
7.4.1 Study Drug Administration .................................................................... 15
7.5 Efficacy Analyses .................................................................................. 16
7.5.1 Overall Response Rate ........................................................................... 16
7.5.2 Progression Free Survival ...................................................................... 16
7.5.3 Time to Progression ............................................................................... 17
7.5.4 Duration of Response ............................................................................. 18
7.5.5 Duration of Clinical Benefit Response .................................................. 18
7.6 Safety Analysis ...................................................................................... 18
7.6.1 Adverse Events ...................................................................................... 19
7.6.2 Laboratory Data ..................................................................................... 20
7.6.3 Vital Signs and Weight .......................................................................... 21
7.6.4 12-Lead Electrocardiogram ................................................................... 21
7.6.5 Prior and Concomitant Medications ...................................................... 21
7.6.6 Protocol Deviations ................................................................................ 22
8 STATISTICAL/ANALYTICAL ISSUES ........................................................ 22
8.1 Handling of Dropouts or Missing Data .................................................. 22
8.2 Interim Analysis and Data Monitoring .................................................. 22
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1 INTRODUCTION
This statistical analysis plan (SAP) was prepared for an abbreviated clinical study report
(aCSR) in accordance with Protocol ONX-2012-001, dated 26June2014 (amendment 3),
and describes the analyses of data collected within the scope of the study. Any changes
that are made to the planned analyses after the SAP is finalized, along with an
explanation as to when and why they occurred, will be noted in the abbreviated clinical
study report produced for the study. Any changes made to the planned analyses that are
in the protocol will be identified and documented in this document.
2 STUDY OVERVIEW
2.1 Overall Study Design
This study is an open–label, Phase 1b/2, multicenter study in which subjects will receive
oprozomib (OPZ) administered orally once daily in combination with dexamethasone
(DEX) on 2 different treatment schedules. Subjects will receive OPZ on Days 1–5 of a
14–day cycle in combination with 20 mg DEX on Days 1, 2, 8, and 9; or OPZ on Days 1,
2, 8, and 9 of a 14–day cycle in combination with 20 mg dexamethasone on Days 1, 2, 8,
and 9. Both the Phase 1b and Phase 2 portions of this trial will be open to subjects with
relapsed and/or refractory multiple myeloma.
Treatment will be administered in 14–day cycles until disease progression, unacceptable
toxicity, or study treatment discontinuation for any reason.
Disease response assessments will be performed every 4 weeks for the first year through
Cycle 26 and then every 8 weeks thereafter according to the IMWG–URC. In addition,
nCR and MR will be assessed per the modified EBMT criteria.
A minimum of 3 subjects will be entered within each dose cohort, to be expanded up to 6
subjects if DLTs are observed. Assessment of DLTs will occur during the first 14 days
of treatment (or Cycle 1) or the first 14 days of treatment with the step-up dose to be
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studies (Cycle 2). Any subject who develops a DLT after receiving at least 1 dose of
OPZ will be considered evaluable. Any subject who does not develop a DLT, but has not
received all planned doses of OPZ and DEX will be considered unevaluable for the dose
escalation decision and will be replaced.
If none of the first 3 subjects in a cohort experiences a DLT in the first cycle, enrollment
will commence at the next planned dose level. If 1 of 3 subjects enrolled in a cohort
experiences a DLT during the first treatment cycle, the same cohort will be expanded up
to 6 evaluable subjects. If 1 of 6 subjects experiences a DLT during the first treatment
cycle, the next cohort will enroll at the next higher dose level. If 2 or more subjects in a
cohort experience a DLT in the first treatment cycle, the MTD will have been exceeded,
additional enrollment within the cohort will cease, and dose escalation will stop.
If 2 or more subjects experience a DLT at a given dose, additional subjects will be added
to the preceding dose group if there are fewer than 6 subjects in that cohort, for a
minimum of 6 subjects treated at that dose in order to determine the MTD. The MTD
will be defined as the highest dose in which a DLT is observed in less than 2 of 6 subjects
At least 6 subjects must be treated at the MTD for a minimum of 1 cycle to establish this
dose as tolerated.
The initial cohort will be entered at a dose level of 210 mg. All subsequent cohorts will
be escalated by 30 mg until the MTD is determined. There will not be a predefined
maximum dose to be studied.
2.2 Study Objectives
2.2.1 Primary Objectives
Phase 1b:
• To determine the MTD and recommended Phase 2 dose (RP2D) of OPZ given
orally, once daily, on 2 different schedules: 5 consecutive days every 14 days
(bimonthly; 5/14) or 2 consecutive days every 7 days (weekly; 2/7) for a 14–day
treatment cycle, both schedules given in combination with DEX.
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• To evaluate safety and tolerability
Phase 2:
• To estimate the overall response rate (ORR), defined as the proportion of subjects
with the best overall response of stringent complete response (sCR), complete
response (CR), near complete response (nCR), very good partial response
(VGPR), and partial response (PR) as defined by the International Myeloma
Working Group–Uniform Response Criteria (IMWG–URC) and modified
European Group for Blood and Marrow Transplantation (EBMT) criteria.
• To evaluate safety and tolerability
2.2.2 Secondary Objectives
• To evaluate PK of OPZ tablet and OPZ ER tablet
• To estimate clinical benefit rate (CBR), defined as ORR plus minimal response (MR), as defined by the EBMT criteria
• To estimate the duration of response (DOR)
• To estimate progression–free survival (PFS)
• To estimate time to progression (TTP)
2.3 Sample Size Justification
For the Phase 1b portion of the study, it is estimated that up to approximately 60 subjects
(approximately 30 subjects per treatment schedule) will be required to determine the
recommended Phase 2 dose for each treatment schedule. This is based on an estimate
that up to 5 cohorts will be enrolled per treatment schedule, with up to 6 evaluable
subjects per cohort.
For the recommended dose group (dose escalation cohort plus Phase 2 cohort), the null
(H0) and the alternative (HA) hypotheses are as follows:
H0: ORRCd ≤ 15%
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HA: ORRCd > 15%
With a sample size of 46 subjects (6 evaluable dose escalation subjects + 40 Phase 2
subjects enrolled at the recommended dose), a 1–sample exact binomial test with a 1–
sided significance level of 5% will have 77% power at an ORR of 30%. If at least 12 of
the 46 subjects have a best overall response of PR or better, then the null hypothesis will
be rejected and it will be inferred that the ORR is > 15%.
The total study sample size will depend on the number of dose levels required to establish
the recommended dose for each schedule and the number of schedules initiated in the
Phase 2 portion of the study. The study will enroll approximately 140 subjects.
3 STUDY ENDPOINTS
3.1 Primary Endpoints
Phase 1b:
• Dose–limiting toxicities identified to determine the MTD and RP2D, defined as the highest dose at which < 33% of subjects experience DLTs after 1 cycle (14 days) of treatment.
• Safety and tolerability
Phase 2:
• Overall response status, to determine whether a subject has a best response of sCR, CR, nCR, VGPR, or PR, as defined by IMWG–URC and EBMT criteria (nCR)
• Safety and tolerability
3.2 Secondary Endpoints
Phase 1b/2:
• Pharmacokinetics of OPZ tablet and OPZ ER tablet
Phase 2:
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• Clinical benefit response status, to determine whether a subject has a best response of sCR, CR, nCR, VGPR, or PR, as defined by IMWG–URC and EBMT criteria (MR and nCR)
• Duration of response
• Progression–free survival
• Time to progression
4 ANALYSIS POPULATIONS
All subjects who receive at least 1 dose of study treatment will be considered evaluable
for both the efficacy and safety analyses (Safety Population). The Safety Population will
be the primary population for all safety and efficacy data presented (Phase 1 and Phase
2).
5 ANALYTIC DEFINITIONS
5.1 Study Day 1
Study day 1 corresponds to the date of the first dose of study drug.
5.2 Study Day
For events, assessments, and interventions after study day 1, study day represents the
elapsed number of days from study day 1, inclusive:
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day
Unless otherwise specified, the timing of all study-related events, assessments, and
interventions will be calculated relative to study day 1. Study day −1 will be the day
before study day 1, and in general for assessments prior to study day 1, study day is
defined as:
Study Day n = (Date of assessment – Date of Study Day 1)
For listings (such as for adverse events) that include the derivation of “days since last
dose,” this is defined as event date – date of last dose. Events that occur on the same day
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as the last dose of study drug will therefore be described as occurring zero days from the
last dose of study drug.
5.3 Baseline
Unless otherwise specified, the baseline value is defined as the last assessment prior to
the first dose of OPZ and DEX.
6 INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES
There are no formal interim analyses planned for this study. A Cohort Safety Review
Committee (CSRC) will review the clinical and laboratory data of each dose cohort
before escalating the OPZ dose to the next dose cohort.
7 STATISTICAL METHODS
7.1 General Considerations
This statistical analysis plan is being generated prior to locking the study database. It
specifies the main efficacy and safety analyses to be performed.
All statistical summaries and analyses will be performed in SAS® version 9.3 or higher
(SAS Institute Inc., Cary, NC, USA) on a PC platform.
In general, summaries of all data will be presented by schedule and dose groups, defined
as initial dose level cohort for phase 1 and recommended dose cohort for phase 2. In
addition, some summaries will include the combined recommended dose cohort from
phase 1 and 2 and total cohorts (all subjects by schedule).
Summary statistics will be provided for selected endpoints. For continuous variables, the
number of subjects with non-missing data (n), mean, standard deviation, median,
minimum, and maximum will be presented. For discrete data, the frequency and percent
distribution will be presented. Unless otherwise indicated, percentages will be calculated
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based upon the number of subjects in the Safety Population in each dose group as the
denominator.
Confidence intervals, when presented, will be constructed at the 95% level. For binomial
variables, exact distribution methods will be employed. The distribution of time-to-event
endpoints will be summarized by Kaplan-Meier method. Quartiles including median will
be estimated by Kaplan-Meier method along with their 95% confidence intervals.
Individual subject data recorded on the electronic case report forms (eCRFs) and any
derived data will be presented by dose cohort and subject in data listings.
7.2 Disposition of Subjects
The following subject disposition information will be summarized for all subjects by each
of the schedule and dose group and for the combined dose groups (total group).
• number of treated subjects
• number (%) of subjects who discontinue from the study drug
• primary reason for study drug discontinuation
• number (%) who had an End of Study visit
• reason for no End of Study visit
7.3 Demographic and Baseline Characteristics
7.3.1 Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized for the
Safety Population.
• Age (years) and age categorized (years) as <65, 65 - <75, and ≥ 75
• Sex
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• Ethnicity
• Race
• Baseline ECOG performance status
• Baseline fertility status
• Baseline weight (kg)
• Baseline height (cm)
7.3.2 Medical History
The number (%) of subjects who experienced a prior disease or disorder will be
summarized by body system for the Safety Population.
7.3.3 Disease Characteristics
The following disease characteristics will be summarized for the Safety Population.
• ISS at initial diagnosis and at Screening
• Time (years) since initial diagnosis, defined as date of informed consent signed
minus date of diagnosis
• Category of multiple myeloma
• Heavy chain and light chain status
• Plasma cell involvement (%) as assessed with bone marrow assessment ( < 50%,
≥ 50%, unknown or missing)
• FISH (standard risk, high risk, unknown or not done)
o High risk: with one of the following abnormalities: t(4;14), t(14;16),
del(17p;13), or 1q21 amplification
o Standard risk: none of the high risk finding
• Baseline β2 microglobulin (mg/L) (< 5.5 mg/L versus ≥ 5.5 mg/L)
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7.3.4 Prior Cancer Therapies
The following prior cancer therapy data will be summarized for the Safety Population:
• Number (%) of subjects with at least one prior:
o Chemotherapy
o Transplant
o Radiotherapy
o No prior therapy
• Number of regimens of prior treatment (1, 2, etc) for multiple myeloma and
number of prior drugs
7.4 Treatments and Medications
7.4.1 Study Drug Administration
The overall extent of study treatment exposure and dose information will be summarized
for the Safety Population for both OPZ and DEX.
• Duration of treatment (weeks), defined as (date of last dose – date of first
dose + 1) divided by 7 for OPZ and DEX
• Total number of treatment cycles during which one full daily dose of OPZ and
DEX was taken by the subject.
• Number (%) of subjects dosed by cycle, where a subject will be considered to
have been dosed in a cycle if the subject receives at least one full daily dose of
OPZ and DEX.
• Total doses received across all cycles of OPZ and DEX
• Dose modifications of study drug based on AE action taken data
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7.5 Efficacy Analyses
All efficacy analyses will be based on the Safety Population. Disease progression as
collected at the end of treatment (end of study visit) as determined by the investigator
will be used for the analysis for PFS, TTP, and DOR.
7.5.1 Overall Response Rate
The overall response rate (ORR) is defined as proportion of subjects for whom the best
overall confirmed response is stringent complete response (sCR), complete response
(CR), near complete response (nCR), very good partial response (vGPR), or partial
response (PR) as defined by International Myeloma Working Group Uniform Response
Criteria (IMWG-URC) and modified European Group for Blood and Marrow
Transplantation (EBMT) criteria (nCR). An estimate of the ORR and its 1–sided 95%
exact binomial confidence interval for each of the recommended dose groups will be
determined. Additionally, the ORR and CBR along with the associated 2–sided 95%
exact binomial confidence intervals will be determined including the recommended dose
group (dose escalation cohort + Phase 2 cohort).
7.5.2 Progression Free Survival
Progression free survival (PFS) is defined as number of months (one month = 30.4 days)
between start of treatment and first evidence of documented disease progression or death
(due to any cause), whichever occurs first. Disease progression will be determined using
IMWG-URC and will be determined by the investigator.
PFS = Earliest date of disease progression, death, or censoring – Date of first
dose + 1 and expressed in months
The duration of PFS will be right–censored for subjects who meet 1 of the following
conditions: 1) starting a new anticancer therapy before documentation of disease
progression or death; 2) death or disease progression immediately after more than
1 consecutively missed disease assessment visit or; 3) alive without documentation of
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disease progression before the data cutoff date. For such subjects, the analysis of PFS
will be right–censored according to the conventions described in Table 1.
Table1: Date of Progression or Censoring for PFS and DOR
Situation Date of Progression or Censoring Outcome
No baseline disease assessments Date of first dose Censored
New anticancer therapy started before documentation of PD or death
Date of last disease assessment prior to start of new anticancer therapy
Censored
Death or PD immediately after more than 1 consecutively missed disease assessment visit
Date of last disease assessment visit without documentation of PD that is before the first missed visit
Censored
Alive and without PD documentation Date of last disease assessment Censored
Death or PD between planned disease assessments
Date of death or first disease assessment showing PD, whichever occurs first
Progressed
Death before first disease assessment Date of death Progressed
PD = progressive disease
Kaplan-Meier method will be used to estimate the distribution of PFS and the median and
other quartiles in addition to the corresponding two-sided 95% confidence intervals.
Duration of follow-up for PFS will be summarized according to the Kaplan-Meier
estimate of potential follow-up also termed “reverse Kaplan-Meier” (Schemper 1996).
7.5.3 Time to Progression
Time to progression (TTP) is defined as number of months between start of treatment to
the first documentation of disease progression. Disease progression will be determined
using IMWG-URC as assessed by the investigator:
TTP = Earliest date of disease progression or censoring – Date of first dose + 1
and expressed in months
The same censoring rules, except for death, as in analysis of PFS will be applied in
calculation of TTP. Subjects who die prior to progressive disease will be censored at the
date of last evaluable response assessment.
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7.5.4 Duration of Response
Duration of response (DOR) will be calculated for subjects who achieve a sCR, CR, nCR,
VGPR, or PR. For such subjects, the duration of overall response is defined as the time
from first evidence of PR or better to disease progression or death due to any cause.
DOR = Earliest date of disease progression, death, or censoring - Date of first
observation of PR or better before confirmation + 1 and expressed in
months
Duration of response will be right–censored for subjects who at least achieve a PR based
on the censoring conventions defined previously for PFS. Analysis of DOR will be
performed using the Kaplan–Meier method. Medians and other quartiles for DOR will be
estimated in addition to the corresponding 2–sided 95% confidence intervals.
7.5.5 Duration of Clinical Benefit Response
Duration of clinical benefit response (CBR) will be calculated for subjects who achieve a
MR or better. For such subjects, the duration of CBR is defined as the time from first
documentation of MR or better to disease progression or death due to any cause. Dates
of progression and censoring will be determined as described for the analysis of PFS.
Duration of CBR = Earliest date of disease progression, death, or censoring -
Date of first observation of MR or better before confirmation + 1 and
expressed in months
The duration of CBR will be summarized descriptively using the Kaplan-Meier method.
The quartiles of the Kaplan-Meier distribution will be used to estimate the median
duration of CBR.
7.6 Safety Analysis
All safety analyses will be based on the Safety population.
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7.6.1 Adverse Events
Each reported AE term will be mapped to a preferred term (PT) and a system organ class
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA).
Treatment-emergent adverse events (TEAEs) are defined as AEs that start on or after the
first day of study treatment and within 30 days of the last day of study treatment. An AE
that is present before the first administration of study treatment and subsequently worsens
in severity during treatment is also considered to be treatment-emergent.
Adverse events will be summarized based on the number (%) of subjects experiencing
events by MedDRA system organ class and preferred term. The denominator for the
percentage will be based on the number of subjects at in the Safety Population (i.e., those
that received at least one dose of study drug).
A subject reporting the same AE more than once will be counted only once when
calculating 1) within a given system organ class, and 2) within a given system organ class
and preferred term combination. For such cases, the maximum National Cancer Institute
(NCI; US) - Common Terminology Criteria for Adverse Events toxicity grade and
strongest causal relationship to study treatment for the event will be used in the incidence
calculations. AEs will also be summarized by severity and by relationship to study drug.
An overall summary of TEAEs will summarize the number (%) of subjects
• with at least one TEAE
• with at least one treatment-related TEAE, defined as related to OPZ or DEX
• with at least one grade 3 or higher TEAE
• with at least one treatment-related grade 3 or higher TEAE, either OPZ or DEX
• with at least one serious AE
• with TEAE leading to discontinuation of study drug, either OPZ or DEX
• with TEAE leading to discontinuation of OPZ
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• who died within 30 days of last dose of study drug
Summaries of the following TEAEs will be provided by SOC and/ or PT unless otherwise
noted:
• all TEAEs
• all TEAs (PT)
• TEAEs by maximum severity
• treatment-related adverse events (OPZ, DEX, and study drug [OPZ/DEX])
• serious TEAEs
• TEAEs that led to permanent discontinuation of study drug (OPZ, DEX and study
drug [OPZ/DEX])
Summaries that are displayed by system organ class and preferred terms will be ordered
by descending order of incidence of system organ class and preferred term within each
system organ class for the total group. Summaries of TEAEs, treatment-related AEs will
also be provided by descending order of incidence of preferred terms in the total group.
All AEs, including TEAEs, will be included in listings by subject.
Listings of AEs determined to be DLTs during the first cycle of Phase 1, serious AEs,
and AEs leading to discontinuation of study drug will be provided.
A summary of the number of deaths and the cause of death, classified by deaths within 30
days of last dose of study drug and deaths more than 30 days after the last dose, will be
provided.
7.6.2 Laboratory Data
All available laboratory results will be included in the subject data listings.
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Selected laboratory test results will be assigned toxicity grades using CTCAE 4.03. A
summary of post-baseline grade 3 or higher laboratory toxicities will be provided. The
laboratory parameters of interest for these summaries are:
Hematology (all decrease) Serum Chemistry (increase except where noted) Hemoglobin ALT Albumin Platelets AST Uric Acid WBC Alkaline Phosphatase Sodium (increase, decrease) Neutrophils (absolute) Total Bilirubin Phosphorus (decrease) Lymphocytes (absolute) Creatinine Potassium (increase,
decrease) Calcium (increase,
decrease) Magnesium (increase, decrease)
Glucose (increase, decrease)
7.6.3 Vital Signs and Weight
Vital sign results including blood pressure, pulse, and temperature will be included in the
subject data listings.
7.6.4 12-Lead Electrocardiogram
Maximum post-baseline and maximum increase from baseline categories of corrected QT
interval results will be summarized.
7.6.5 Prior and Concomitant Medications
All prior and concomitant medications will be coded using WHO Drug Dictionary.
Concomitant medications are defined as medications with start date or end date on or
after the date of first dose and before the date of the last dose + 30 days or are ongoing at
the time of first dose. Prior medications are defined as medications with a stop date
before the date of first dose.
Concomitant medications will be summarized by generic name.
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7.6.6 Protocol Deviations
Protocol deviations will be included in the subject data listings. Major protocol
deviations will be either captured on the designated eCRF (e.g., eligibility
violations) or identified through data review and surveillance.
8 Statistical/Analytical Issues
8.1 Handling of Dropouts or Missing Data
The handling of dropouts and missing disease status assessments for the efficacy
variables is described in their definitions.
Missing or partially missing dates will not be imputed at data level. However,
assumptions for missing or partially missing dates for important variables will be made to
allow inclusion of appropriate data records in the analyses.
If a medication date or time is missing or partially missing, so it cannot be determined
whether it was taken prior or concomitantly, it will be considered as a prior, concomitant,
and a post-treatment medication.
If the partial AE onset date information does not indicate whether the AE started prior to
treatment or after the TEAE period, the AE will be classified as TEAEs.
If the start day of subsequent anti-cancer therapy is missing, it will be assumed to be the
first day of the month.
8.2 Interim Analysis and Data Monitoring
The CSRC will review the clinical data of each dose cohort after three subjects have been
treated for at least one cycle during phase 1 of the study. Based on the number of
subjects with dose-limiting toxicity, escalation to the next higher OPZ dose may occur,
the cohort may be expanded to six subjects, or dosing at that dose level may stop and the
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next-lower dose cohort may be expanded. The committee must agree that dose escalation
to the next cohort is appropriate before it proceeds.